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Stroke overview: Current and
future treatments
Sandra Narayanan, MD
Assistant Professor, Departments of Neurosurgery & NeurologyWayne State University School of Medicine
Director, Interventional Neuroradiology,
Detroit Medical Center
March 4, 2013
Disclosures
• None
• Discussion of investigational devices for acute stroke treatment
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Objectives
• To become familiar with the spectrum and management of acute ischemic and hemorrhagic stroke subtypes.
• To correctly identify the signs/symptoms of stroke and perform a stroke-centered neurological exam/National Institutes of Health Stroke Scale (NIHSS).
• To know the time windows and treatment options for acute stroke interventions.
True or False?
• Acute stroke is the 3rd leading cause of death.
• The time limit for IV-tPA is 4.5 hours.
• IV-tPA is equally effective throughout the first 3 hours of stroke.
• Lacunar infarcts do not benefit from IV-tPA.
• The majority of patients with aneurysms will have a SAH.
• The majority of SAH patients have an aneurysm.
False
True
False
False
False
True
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Epidemiology
• 4th leading cause of death
– 2202 fewer deaths from stroke in 2008 than in 2007
• 795,000 strokes/year in U.S.
– ~560,000 are first-time events
– 60,000 more strokes in women than men/year
– 1 in 4 patients dies within 1 year
– 30-50% of survivors do not regain functional independence
– 15-30% of survivors permanently disabled
• Cost of stroke in 2010: $73.7 billion
AJNR 2009;30:649-61.
Panorama of stroke
• Ischemic stroke: 85%– Cardioembolic
– Large-vessel atherosclerosis
– Small-vessel occlusion
– Other determined
– Undetermined
• Hemorrhagic stroke: 15%– Subdural
– Intraparenchymal
– Subarachnoid
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Etiologies of ischemic stroke
• Atherosclerotic risk factors– HTN– DM– Hyperlipidemia– Tobacco abuse (in past 5 years)– XRT– Homocystinuria
• Dissection– Trauma– Chiropractic manipulation
• Hematologic– Sickle cell disease– DVT– History of miscarriages– Livedo reticularis– Asymmetric radial pulses
• Cardioembolism– Atrial fibrillation– Ischemic/dilated cardiomyopathy– Mural thrombus/mass– IVDU– Atrial septal aneurysm– Paradoxical embolism/DVT/PFO
• Association w/ Valsalva
– Cancer
• Miscellaneous– Oral contraceptives– Recurrent headaches– Recent infection– Peripartum– HIV+– EtOH use– Family hx of any of above/premature
stroke– Hearing loss– Uterine/bowel rupture or pneumothorax
(suggests connective tissue disorder)
Signs of posterior circulation ischemia
• Syndrome “doesn’t fit” a vascular territory– This may not be an MCA infarct– This may not be an arterial infarct– Top-of-basilar syndromes usually embolic → infarcts in multiple vascular
territories• May be nonfocal/subtle
– Drowsiness– Partial Wallenberg syndrome– “Blurry vision”
• Homonymous hemianopia• Diplopia• Amaurosis fugax• Transient visual obscurations (TVOs)
• Often progressive• Fluctuation not uncommon• Declining level of consciousness heralds worsening prognosis• Recent headache/neck pain
– Dissection– Migrainous stroke– Venous thrombosis
• Seizure less common but does occur– Embolic etiology– Venous thrombosis
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Common signs of posterior circulation
ischemia
• Ataxia
• Lethargy – may be progressive
• Dysarthria – pa-ta-ka
• Diplopia
• Cranial nerve deficits
• Gaze deviation – away from stroke
• Crossed signs – ipsilateral facial droop/numbness
– contralateral hemiparesis/numbness
NIHSS
http://learn.heart.org
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Knowledge of tPA for acute stroke among Michigan adults
• 32.2% aware of tPA
– 52.7% knew of 3-hour window
– 1 in 6 adults aware of time-sensitive nature
• Awareness greater among middle-aged adults (55-64 yrs), women, Caucasians, higher income
• 27.6% - can state 3 warning signs
Stroke 2009;40:2564-7.
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EMS arrival makes a difference
• 22.3% of U.S. has access to PSC within 30 min. (55.4% within 60 min.)
• Air ambulances increase likelihood of arriving within 60 min. to 79.3%
• Austria: 21,712 stroke pts (4.1% helicopter) –OR 3.6 of receiving thrombolysis vs. indirect ambulance w/ ER MD (OR1.5)
• Pts aged 15-49 yrs: arrival by ambulance is associated with receiving stroke intervention (p0.005)– No difference if presenting hospital had Primary
Stroke Center (PSC) certification
Time is brain. Quantified.
• Typical #neurons in human forebrain = 22 billion
• In large-vessel stroke, 1.9 million neurons are lost every minute without recanalization
• Brain ages 3.6 years/hour of untreated stroke
Stroke 2006;37 (1):263-6.
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IV-rtPA (recombinant tissue plasminogen activator)• Approved by FDA in 1995 for ischemic stroke within <3
hrs. onset
• ↓incidence favorable outcome at 3 mo. with ↑time interval from stroke onset to start of treatment
• Nationwide tPA rates 2-3%
0-90 min 91-180 min 181-270 min 271-360 min
Number needed to tx for benefit
(NNTB)
3.6 4.3 5.9 19.3
Number needed to tx for harm (NNTH)
65 38 30 14
Help-to-harm 18.1 8.8 5 0.7
Stroke 2009;40(6):2079-84.
Get With the Guidelines
• American Stroke Association: Goal Door-to-Needle (DTN) time <60 min >80% of time
• Of 129,431 stroke pts. presenting within 3 hrs. of sxonset, 24, 504 (19.7%) received IV-tPA
• Mean DTN 79.3 min, median 78 min
• Group with DTN <60 min were more likely to – meet door-to-CT complete <25 min.
– be at hospital with annual stroke volume >300 pts. (p 0.003)
– be at hospital giving IV-tPA >20 times/yr. (p <0.001)
– older (p <0.001), female (p 0.001), African-American (p 0.001)
– arriving by ambulance (p 0.1275) on-hours (p <0.001)
Circulation 2011;123(7):750-8.
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Improved outcomes in DTN <60 min
DTN <60 min(n=6790)
DTN >60 min(18,714)
P value
In-hospital mortality 8.6% 10.4% <0.001
Any tPA complic 8% 9% 0.0065
sICH 4.7% 5.6% 0.0017
After adjustment, each 15-min. reduction in door-to-needle
time was associated with 5% lower odds of dying.
Circulation 2011;123(7):750-8.
Stroke workup
• CT head w/o contrast
• MRI head w/o gadolinium
• MRA/CTA head/neck
• 2D echocardiogram w/ bubble study eval. mural thrombus/atrial septal aneurysm/PFO
• Telemetry eval. arrhythmia
• Fasting lipids
• (Trans-esophageal echocardiogram eval. left atrial appendage thrombus/aortic arch)
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Stroke workup in patients <55 yrs.
• CBC, chemistry, ESR, CRP• PT/PTT/INR• RPR/VDRL• Homocysteine, lactic acid, Lp(a)• Toxicology• Sickle cell prep• Pregnancy test• EKG• CT head w/o contrast• MRI head w/o gadolinium• MRA/CTA head/neck• TTE/TEE with bubble study• CSF
• ANA, ANCA, cryoglobulins, HIV
• Transcranial Doppler
• Cerebral angiography
• Brain/meningeal biopsy
• Hypercoagulable w/u– Protein C & S– Antithrombin III– Activated Protein C resistance– Factor V Leiden mutation– Antiphospholipid Ab– Prothrombin 20210A gene
mutation– Fibrinogen– MTHFR C677T
Intra-arterial therapy (IAT): why? when?
• Poor IV-rtPA recanalization rates for proximal arterial occlusion– Internal carotid artery (ICA): 10%– Proximal middle cerebral artery (MCA): 24-30%
• IA-rtPA: local delivery of fibrin-selective agent → less systemic effect of hypofibrinogenemia
• Mechanical strategies– ↓use of thrombolytics: possibly↓symptomatic
intracranial hemorrhage (sICH)– Extend treatment window– ↑ surface area accessible to fibrinolytic agents– Clot retrievers possibly more efficient at removing
mature clot or cholesterol/calcium emboli
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Acute stroke: Interventional tools
• Merci (Mechanical Embolus Retrieval in Cerebral Ischemia) retriever
• Thromboaspiration(Penumbra)
• Stent• Balloon angioplasty• Stentriever
– Solitaire– Trevo– 3D Separator– Mindframe– Surpass– Revive IC
• IV-rtPA
• Intra-arterial therapies
<4.5 hours <8 hours
<6 hours• Intra-arterial therapies
• IA-rtPA• Mechanical
Thrombectomy is time-dependent
Neurology 2009;73:1066-72.
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Mechanical thrombectomy
MERCI
- Mechanical grasp of clot with a cork screw like device- First device approved for mechanical extraction HDE- Benchmark for all future mechanical device trials
MERCI PENUMBRA
- Proximal aspiration of clot in fragments- Safer and more effective than MERCI- Used in conjunction with other methods
Mechanical thrombectomy
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MERCIPENUMBRA
- Mechanical clot extraction by a self-expanding, fully retrievable stent- Safer and more effective than MERCI, comparable to Penumbra- Used in conjunction with other methods (SOLUMBRA)- Faster recanalization times
SOLITAIRE
Mechanical thrombectomy
MERCIPENUMBRA
-Mechanical clot extraction by self-expanding, fully retrievable stent- Similar in design, technique, outcomes to SOLITAIRE- Used in conjunction with other methods
SOLITAIRETREVO
Mechanical thrombectomy
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MERCIPENUMBRA
- Mechanical clot extraction by a self-expanding fully retrievable stent with internal partitions to grasp clot- Similar in intent with stentrievers, but different in design - Currently under investigation
SOLITAIRETREVO 3D RETRIEVER
Mechanical thrombectomy
TRIAL Recanalization SICH mRS <2 Mortality
NINDS - 6% 28% 24%
PROACT II 66% 10.9% 40% 25%
IMS II 60% 9.9% 46% 16%
MERCI 48% 7.8% 28% 44%
PENUMBRA 82% 11% 25% 33%
POST (PENUMBRA) 84% 7% 40% 25%
MULTI MERCI 68% 9.8% 36% 34%
TREVO 78% 5% 55%
SWIFT (SOLITAIRE) 83% 11% 58% 18%
TREVO 2 86% 6.8% 40%
IMS III 65-81% 6.2% 40.8% 19.1%
Acute stroke clinical trials
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LICA occlusion
Intracranial hemorrhage
SubarachnoidSubdural IntraparenchymalIntraventricular
Intra-axialExtra-axial
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Saccular aneurysms
• Location– Anterior communicating A: 30-35%
– Posterior communicating A: 25%
– MCA bifurcation: 20%
– BA apex: 10%
• 2-5% population
• Factors influencing aneurysm rupture:– Cocaine/amphetamine use
– Uncontrolled HTN
– Smoking
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Pial AVMs: Epidemiology
• Congenital
• 3rd-6th decades, males=females
• Rarely familial (Osler-Weber-Rendu & Sturge-Weber syndromes)
• 2% multiple
– Wyburn-Mason syndrome
– Osler-Weber-Rendu syndrome
Aneurysmal subarachnoid hemorrhage (SAH)
• 30,000 cases/year
• 30-50% patients die before arriving to hospital
• 50% of survivors sustain irreversible brain injury
• Females > males
• Complications: rebleeding vasospasm, strokes, seizures, low sodium, hydrocephalus
• Risk of re-bleeding if aneurysm not secured: 2%/day x first 48 hours, 1-2%/day x first 2 weeks, 50% at 6 months
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Treatment of intracranial aneurysms
• Endovascular
– Coil embolization
– Balloon remodeling + coiling
– Stent-assisted coiling
– Onyx®-500 embolization
• Surgical clip ligation
Angiography – Right internal carotid artery aneurysm
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Pial AVMs: Pathophysiology
• Embryonic error of angiogenesis at capillary level
• Serpiginous mass of dilated feeding arteries, nidus, dilated draining veins
• Electron microscopy: abnormal elastic lamina/internal lamella, hyalinized venous walls
Pial AVMs: Presentation
• Presentation– ICH – 50% (ICH>IVH>SAH)
– Seizures – 25%
– Ischemia (steal phenomena)
– Headaches
• Annual hemorrhage rate: 1-4%
• Mortality after 1st ICH: 10-29% (up to 50% for posterior fossa ICH)
• Re-hemorrhage rate in 1st year: 6-17%
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Pial AVMs: CT/MR
• CT– Slightly hyperdense serpiginous vascular
structures
– Calcification (30%)
• MR– Gliosis/adjacent atrophy from steal
– Hemosiderin from prior micro-hemorrhages
– Slow-flowing components poorly demonstrated by non-enhanced MRA
– Mass effect uncommon (unless ICH present)
Pial AVMs - Calcifications
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Pial AVMs: Angiography
• Sine qua non: early draining vein
• 85% supratentorial (MCA>ACA>PCA territories), 15% infratentorial
• 10-15% have pre-/intra-nidal aneurysms
• 10-15% may also have dural (ECA) supply
• Gold standard to evaluate for small AVM
Spetzler-Martin III AVM
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Spetzler-Martin III AVM
Spetzler-Martin III AVM
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Spetzler-Martin III AVM
Spetzler-Martin III AVM
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Spetzler-Martin III AVM
AVMs: Treatment
• Surgery
• Pre-operative embolization (liquid embolic agent/glue) + surgery
• Embolization alone (if few feeders)
• Radiosurgery
• Observation
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Dural AVFs
• AV shunt involving dura, not parenchyma• Females:males::3:1• Acquired
– Idiopathic (most common)– Venous thrombosis– Trauma– Infection– Hypercoagulable state– Prior neurosurgery
• Presenting symptoms– Pulsatile tinnitus– HA– Cranial nerve palsies– Focal neurological deficits– Dementia (venous congestive encephalopathy)
Dural AVFs
• Feeders
– ECA branches
– Tentorial/dural branches ICA
– Meningeal branches VA
– Pial branches (rarely)
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Angiography
• Normal on post-bleed-day #0 and #10
• Angiogram 3 months later: +duralarteriovenous fistula
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